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Linking microRNA dynamics to mental health: Assessing the contribution of brain expressed miRNAs to the increased risk for psychiatric disorder in 22q11.2DS subjects.


   Cardiff School of Psychology

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  Prof L Wilkinson  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

Genetic factors, in tandem with life events, make a key contribution to mental health and variations in the genetic code can increase susceptibility to falling ill across a range of psychiatric disorders, including depression, anxiety and psychosis. Some of the most damaging genetic effects are seen in 22q11.2DS (also known as DiGeorge syndrome or velocardiofacial syndrome) in which a stretch of DNA and associated genes is missing on chromosome 22. These individuals present with a variety of physical and psychological challenges. Subjects with 22q11.2DS often develop psychiatric symptoms, with some reports indicating penetrance in as much as 75-90% of the population with approximately 15-25% being diagnosed with schizophrenia. The markedly high penetrance of 22q11.2DS for psychiatric disorder has led to much research into pathogenic mechanisms that may mediate the increased risk, the rationale being that understanding the biological basis of the psychopathology of 22q11.2DS may reveal mechanisms of common relevance to psychiatric disorder and also targets for therapeutic intervention. In this project we will use human induced pluripotent stem cell (iPSC)-derived neurons to address the hypothesis that abnormalities in the metabolism of microRNAs (miRNAs) in brain contribute to the increased risk for psychiatric disorder in 22q11.2DS. miRNAs are small single stranded bits of RNA between 19-24 nucleotides long that impact on gene function by interacting with mRNA during transcription, in the majority of cases by inhibiting mRNA. We strongly suspect a significant contribution of miRNAs to the 22q11.2DS phenotype due to the presence of the gene DGCR8 (DiGeorge Critical Region 8) in the deleted interval (DGCR8 is a master controller of miRNA biosynthesis), the enrichment of miRNAs risk variants in recent psychiatric genetics case-control association studies and the finding that reduced DGCR8 can mimic 22q11.2DS phenotypes. The student will gain skills, experience and ownership across a wide range of unique assets and cutting-edge experimental approaches and tools. These will include utilisation of banked 22q11.2DS and control iPSC, training in cell culture methods to differentiate neurons from human iPSC, miRNA profiling using bespoke sequencing methods, training in the most up-todate bioinformatic approaches, CRISPR-mediated genome editing, manipulation of miRNAs (e.g. expression of shRNA or miRSponges) and functional analysis using multi-electrode arrays. In all cases, the relevant methodologies are established in the home laboratory and the student will be supported in their training and in developing an increasing independence by the Wilkinson/Harwood research group. The work will be in collaboration with Takeda Pharmaceutical Company Limited and will take advantage of the ongoing Cardiff-Takeda Drug Discovery Partnership led by Lawrence Wilkinson with Adrian Harwood as co-PI, offering access to Takeda expertise and experimental tools as well as a secondment to Takeda in Tokyo during the PhD. The student will have full input to the experimental designs to include; miRNA profiling of 22q11.2DS patient iPSC-derived neurons (using bespoke sequencing methods to overcome the short read lengths) followed by a bioinformatic analysis to link differently expressed miRNAs to their target mRNAs including an enrichment analysis for known risk gene variants. This will identify the key regulatory miRNA associated with psychiatric symptoms. To confirm the contribution of low dosage DGCR8 specifically to the pattern of miRNA changes in 22q11.2DS cells we will CRISPR-engineer DGCR8 heterozygous cells for comparison. In a final set of experiments we will increase candidate disease-relevant miRNAs by expression of small hairpin RNA (shRNA) or decrease them by expression of miRSponges and examine effects on gene expression and neuronal function.

Applications open on 2nd September 2022 and close at 5.00pm on 2nd November 2022.

Studentships will be 4 years full time. Part time study is also available. 


Funding Notes

This studentship is funded through GW4BioMed2 MRC Doctoral Training Partnership. It consists of UK tuition fees, as well as a Doctoral Stipend matching UK Research Council National Minimum (£16,062 p.a. for 2022/23, updated each year).
Additional research training and support funding of up to £5,000 per annum is also available.

References

About the GW4 BioMed2 Doctoral Training Partnership
The partnership brings together the Universities of Bath, Bristol, Cardiff (lead) and Exeter to develop the next generation of biomedical researchers. Students will have access to the combined research strengths, training expertise and resources of the four research-intensive universities, with opportunities to participate in interdisciplinary and 'team science'. The DTP already has over 90 studentships over 6 cohorts in its first phase., along with 20 students in its second phase.
Funding
This studentship is funded through GW4BioMed2 MRC Doctoral Training Partnership. It consists of UK tuition fees, as well as a Doctoral Stipend matching UK Research Council National Minimum (£16,062 p.a. for 2022/23, updated each year).
Additional research training and support funding of up to £5,000 per annum is also available.
Eligibility
Residency: The GW4 BioMed2 MRC DTP studentships are available to UK and International applicants. Following Brexit, the UKRI now classifies EU students as international unless they have rights under the EU Settlement Scheme. The GW4 partners have all agreed to cover the difference in costs between home and international tuition fees. This means that international candidates will not be expected to cover this cost and will be fully funded but need to be aware that they will be required to cover the cost of their student visa, healthcare surcharge and other costs of moving to the UK to do a PhD. All studentships will be competitively awarded and there is a limit to the number of International students that we can accept into our programme (up to 30% cap across our partners per annum).
Academic criteria: Applicants for a studentship must have obtained, or be about to obtain, a UK degree, or the equivalent qualification gained outside the UK, in an appropriate area of medical sciences, computing, mathematics or the physical sciences. Please check the entry requirements of the home institution for each project of interest before completing an application. Academic qualifications are considered alongside significant relevant non-academic experience.
English requirements: If English is not your first language you will need to meet the English language requirements of the university that will host your PhD by the start of the programme. Please refer to the relevant university for further information.
How to Apply
A list of all the projects and how to apply is available on our website at gw4biomed.ac.uk. You may apply for up to 2 projects.
Please complete an application to the GW4 BioMed2 MRC DTP for an ‘offer of funding’. You may also need to make an application for an 'offer to study' to your chosen institution(s) – further details are on the website.
Please complete the online application form by 5.00pm on Wednesday, 2nd November 2022. If you are shortlisted for interview, you will be notified by Friday 16th December 2022. Interviews will be held virtually on 25th and 26th January 2023.
Further Information
For informal enquiries, please contact GW4BioMed@cardiff.ac.uk
For project related queries, please contact the respective supervisors listed on the projects.
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